Preparation of fluorinated organic compounds

ABSTRACT

This invention relates to the fluorination of carboxylic acids with xenon difuoride in the presence of hydrogen fluoride. Novel fluorinated compounds containing aliphatic unsaturation are also disclosed.

BACKGROUND OF INVENTION

This application is directed to the fluorination of organic compounds.More specifically, there is disclosed a process for thefluoro-decarboxylation of carboxylic acid compounds.

Attempts to effect the fluorination of organic compounds employingelemental fluorine as the fluorinating agent have resulted in a highdegree of fluorolysis and consequently in low yields of desiredfluorinated products. Such processes employing solid catalyst masseshave proved to be exceedingly cumbersome and difficult to control. Onemethod for fluorinating an organic compound is disclosed in U.S. Pat.No. 2,549,565. This process comprises separately and simultaneouslyinjecting the organic compound and elemental fluorine (gas) into amolten mass consisting of from 20 percent to 70 percent of silvermonofluoride and from 80 percent to 30 percent of silver difluoridemainained at a temperature between 200° C. and 500° C.

U.S. Pat. No. 2,702,306 discloses another method of producing organicfluorine compounds. This method consists of reacting halogen fluorideswith fluorinatable organic materials, wherein the halogen fluoride ismixed with hydrogen fluoride in concentrations of 10 to 90 percent byweight halogen fluoride and contacting this mixture in the liquid phasewith the fluorinatable organic material.

U.S. Pat. No. 3,221,069 discloses a method in which a halogen atom canbe introduced into an aromatic compound. This process comprises heatingan aromatic carboxylic acid halide at a temperature of from about 200°C. to about 400° C. in the presence of a palladium catalyst.

The production of fluorine-substituted aromatic compounds has beenaccomplished by utilizing XeF₂ in liquid CCl₄ solution and carrying outthe substitution at extremely low temperatures, such as -70° C. Afterthe substitution reaction is complete, the solvent is then removed.Unfortunately, the substitution reaction is quite slow and the reactionequipment is expensive.

Yet another process of producing a fluorine-substituted aromaticcompound is disclosed in U.S. Pat. No. 3,833,581. This process comprisesthe step of reacting certain aromatic compounds in the vapor phase withxenon difluoride vapor at a temperature of about 200° C. and a moleratio of xenon difluoride to said aromatic compound of no greater thanone. Unfortunately, this process requires expensive reaction vesselsthat can cool the reactants to -78° C.

Halogenated organic compounds have previously been prepared byhalo-decarboxylation reactions. In the "Hunsdiecker reaction" the silversalt of a carboxylic acid is reacted with a halogen, which displaces thecarboxyl group (see Wilson, C. V., Organic Reactions, 9, 332 [1957]). Inanother halo-decarboxylation reaction, an ionic halide salt is reactedwith a carboxylic acid in the presence of lead tetraacetate (Kochi, J.K., J. Am. Chem. Soc., 87, 2500 [1965]). But these halo-decarboxylationreactions are limited to halogens other than fluorine.

SUMMARY OF THE INVENTION

The present invention provides a process for fluorinating an organiccompound which comprises reacting a carboxylic acid with xenondifluoride in the presence of hydrogen fluoride, wherein said carboxylicacid is of the formula: ##STR1## wherein R, R', and R" are each,individually, a radical selected from the group consisting of hydrogen;halo; carboxyl; alkyl of 1 to 25 carbon atoms; alkoxy of 1 to 25 carbonatoms; aryl-substituted alkyl, alkenyl or alkynyl of 7 to 32 carbonatoms; aryl of from 6 to 14 carbon atoms; aryloxyalkyl of 6 to 32 carbonatoms; alkyl substituted aryl of 7 to 32 carbon atoms; alkenyl of 2 to25 carbon atoms; and alkynyl of 2 to 25 carbon atoms, said radical beingunsubstituted or substituted by one or more halo, carboxyl, acyl,acyloxy, nitro, amino or acylamino groups.

Surprisingly, when the R, R' or R" radical contains aliphaticunsaturation, fluorination occurs only at the carboxyl site and theunsaturated bonds remain intact.

There are also provided, in accordance with the process of theinvention, novel unsaturated compounds of the formula: ##STR2## whereinm and n are integers of at least 1, such that the sum of m+n is from 2to 24; the bond represented by the dotted line may be hydrogenated; andR"' is hydrogen, halo, acyl, acyloxy, nitro, amino or acylamino. Thecompounds are useful as pesticides.

The novel unsaturated compounds can be prepared, according to theprocess of this invention, by fluorinating a carboxylic acid of theformula: ##STR3##

DESCRIPTION OF THE PREFERRED EMBODIMENT

The present invention involves the fluorination of carboxylic acids.More specifically it relates to the reaction of xenon difluoride withcarboxylic acids in the presence of hydrogen fluoride, resulting in aselective substitution of the carboxyl group with fluorine. For example,phenylacetic acid is reacted with xenon difluoride in the presence ofhydrogen fluoride to produce benzyl fluoride.

The carboxylic acid compounds which are fluorinated in the process ofthe present invention are of the structural formula: ##STR4## where R,R' and R" are as described above. A preferred aryl moiety in the groupsR, R' and R" is phenyl. Examples of carboxylic acids which can befluorinated by the process of the invention include acetic acid,propionic acid, palmitic acid, capric acid, phenylacetic acid,phenylpropionic acid, hydrocinnamic acid, 2-iodomalonic acid, octanoicacid, ethoxyacetic acid, 15-[4-(carboxymethylene)phenyl]pentadecanoicacid methyl ester, 4-phenylbut-3-enoic acid, 4-carboxyphenylacetic acid,4-nitrophenoxyacetic acid, 1,18-octadec-8-endioc acid mono methyl ester,1,18-octadec-8-yndioic acid monomethyl ester and iodoacetic acid.

The resultant fluorinated compounds in which at least one of R, R' andR" is carboxyl, halo, aryl or aryloxy are useful as pharmaceuticalintermediates. Compounds in which at least one of R, R' and R" is alkyl,alkenyl, alkynyl or aryl-substituted alkynyl are useful as pesticides.Compounds in which at least one of R, R' and R" is alkoxy are useful asindustrial solvents. Compounds in which at least one of R, R' and R" isaryl-substituted alkyl or alkyl-substituted aryl are useful as NMRimaging agents. Compounds in which at least one of R, R' and R" isaryl-substituted alkenyl are useful as polymer additives.

If desired, one may carry out the fluorination according to the processof the invention using radioisotopic fluorinating agents, i.e. xenondifluoride and hydrogen fluoride in which the fluorine is ¹⁸ F, toproduce compounds useful as radiopharmaceuticals, e.g. heart imagingagents. Particularly useful for such applications are compounds in whichat least one of R, R' and R" is alkenyl, alkynyl aryl-substituted alkylor alkyl-substituted aryl.

In accordance with the preferred embodiment, the carboxylic acid isplaced in a suitable reactor and the xenon difluoride is then added.Thereafter, the hydrogen fluoride is introduced to the reactants, forexample, by bubbling through the reaction mixture. Preferably, themixture is stirred to insure sufficient contact of the reactants. Afterthe reaction is complete, water or a dilute base solution is charged tothe reactor. The organic layer is then removed and the fluorinatedproduct is isolated.

The reaction can be carried out in a conventional reaction vessel.Preferably, the reaction vessel is a closed vessel equipped with meansfor stirring the reaction mixture and for controlling the temperature ofthe reaction mixture as well as means for introducing the hydrogenfluoride into the reaction mixture, e.g. a sparging tube. Since hydrogenfluoride will react with glass, the reaction vessel is preferably notglass lined.

The xenon difluoride can be provided to the reaction mixture in anamount from about 0.7 to 1.3 moles per mole of carboxylic acid,preferably from about 0.9 to 1.1 moles per mole of carboxylic acid.

The amount of hydrogen fluoride introduced to the reaction is notnarrowly critical as long as a sufficient amount of hydrogen fluoride isbrought into intimate contact with reactants to catalyze the reaction.This can be achieved by slowly bubbling hydrogen fluoride through thereaction mixture at the start of the reaction.

The temperature of the reaction between the xenon difluoride, carboxylicacid and hydrogen fluoride is not narrowly critical. Typically, thereaction can be conducted at a temperature of from 0° C. to 60° C.Preferably, the reaction is conducted at room temperature.

The reaction time can vary depending on the starting materials, reactionconditions and volume of reactants. Typically, the reaction proceeds tocompletion in about 1 to 24 hours.

The pressure at which the reaction is carried out has not been found tobe critical, however, the reaction can be conducted at atmospheric orsuperatmospheric pressures, preferably at atmospheric.

Advantageously the reaction can be carried out in the presence of asolvent. It will be apparent to those skilled in the art anyconventional solvent is suitable as long as its presence does notinterfere with the fluorination reaction. Chlorinated solvents aregenerally preferred. Some examples are methylene chloride, chloroformand carbon tetrachloride.

The following examples are supplied in order to illustrate, but notnecessarily to limit, the process of the present invention.

EXAMPLE 1

Preparation of 12-Fluoro-1-(4-iodophenyl)-4-dodecyne). A solution of 6ml of dichloromethane containing 0.2 grams (0.5 mM) of an acid of thefollowing structural formula: ##STR5## was placed in a plastic bottlewhich was connected to a drying tube and a hydrogen fluoride cylinder.After XeF₂ (0.21 g, 1.25 mM) was added, hydrogen fluoride was added.Several drops of liquid came out of the hydrogen fluoride container andwent into the reaction bottle. The reaction mixture formed two layers.The mixture was stirred for five hours at room temperature and then themixture was poured into ice water. The reaction mixture was thenextracted with ethyl ether. The ether extract was washed with water andbrine. The mixture was then dried over sodium sulfate, the solvent wasremoved to give 0.22 grams of crude product. The major product (0.07grams) was isolated by high pressure liquid chromotography on a C-18reverse phase column. Its ir spectrum and nmr spectra (H-1, C-13 andF-19) were consistent with the structure below: ##STR6## High resolutionmass spectroscopy showed a molecular ion at 386.0910 M/e which wasconsistent with the calculated value of 386.09058 for C₁₈ H₂₄ FI. It wasquite surprising that fluorination occurred selectively at the carboxylsite and that no fluorination occurred at the site of acetylenicunsaturation.

EXAMPLES 2-11

In a manner similar to that of Example 1, the carboxylic acids listed asstarting materials in Table I are fluorinated in the presence of xenondifluoride and hydrogen fluoride. In Examples 5, 9 and 10, the xenondifluoride and hydrogen fluoride employed incorporate radioisotopicfluorine, i.e. ¹⁸ F.

                                      TABLE I                                     __________________________________________________________________________         Starting Material    Product and                                         Example                                                                            and Formula          Formula                                             __________________________________________________________________________    2    2-iodamalonic acid   difluoroiodomethane                                      HOOCCHICOOH          FCHIF(or ICHF.sub.2)                                3    octanoic acid        fluorooctane                                             CH.sub.3 (CH.sub.2).sub.7 COOH                                                                     CH.sub.3 (CH.sub.2).sub.7 F                         4    ethoxyacetic acid    ethoxyfluoromethane                                      CH.sub.3 CH.sub.2 OCH.sub.2COOH                                                                    CH.sub.3 CH.sub.2 OCH.sub.2 F                       5    15-[4-carboxymethylene)                                                                            .sup.18 F-labeled 15-[4-                                 phenyl]pentadecanoic (fluoromethyl)phenyl]                                    acid methyl ester    pentadecanoic acid                                        ##STR7##                                                                                           ##STR8##                                           6    4-phenylbut-3-enoic  3-fluoro-1-phenyl-1-                                     acid                 propene                                                  CHCHCH.sub.2COOH     CHCHCH.sub.2 F                                      7    4-carboxyphenylacetic                                                                              4-(fluoromethyl)-                                        acid                 benzoic acid                                              ##STR9##                                                                                           ##STR10##                                          8    4-nitrophenoxyacetic 4-(fluoromethyoxy)-                                      acid                 nitrobenzene                                              ##STR11##                                                                                          ##STR12##                                          9    1, 18-octadec-8-     .sup.18 F-labeled 17-                                    endioic acid mono-   fluoroheptadec-8-                                        methyl ester         enoic acid                                               HOOC(CH.sub.2).sub.7CHCHCH.sub.2).sub.7 COOCH.sub.3                                                .sup.18 F(CH.sub.2).sub.7 CHCH(CH.sub.2).sub.7                                COOH                                                10   1, 18-octadec-8-     .sup.18 F-labeled 17-                                    yndioic acid mono-   fluoroheptadec-8-                                        methyl ester         ynoic acid                                               HOOC(CH.sub.2).sub.7CC(CH.sub.2).sub.7 COOCH.sub.3                                                 .sup.18 F(CH.sub.2).sub.7 CC(CH.sub.2).sub.7                                  COOH                                                11   iodoacetic acid      fluoroiodomethane                                        ICH.sub.2 COOH       ICH.sub.2 F                                         __________________________________________________________________________

I claim:
 1. The compound of the formula: ##STR13##
 2. A process forfluorinating a carboxylic acid comprising reacting a carboxylic acid ofthe formula: ##STR14## with xenon difluoride in the presence of hydrogenfluoride.